Method of producing a product between meso-inositol and nicotinic acid



United States Patent 3,418,325 METHOD OF PRODUCING A PRODUCT BETWEEN MESO-INOSITOL AND NICOTINIC ACID Bo Thuresson af Ekenstam, Molndal, and Bror Giista Pettersson, Karlskoga, Sweden, assignors to Aktiebolaget Bofors, Bofors, Sweden No Drawing. Filed Dec. 27, 1965, Ser. No. 516,744 3 Claims. (Cl. 260295.5)

ABSTRACT OF THE DISCLOSURE Meso-inositol pentanicotinate is prepared by the controlled hydrolysis of meso-inositol hexanicotinate in acidic aqueous solution. The new compound exhibits the same desirable pharmacological properties of the hexanicotinate with a considerable reduction in such undesirable side effects as flushing and prickliness.

The present invention relates to a method of producing a product between mesq-inositol and nicotinic acid. Nicotinic acid is a component in the B-vitamin complex and has proved to be of considerable biochemical significance in different biological systems. Moreover, nicotinic acid has a directly vasodilating effect and is, among other things, of considerable significance to the metabolism of fats and carbohydrates. Nicotinic acid also influences the cholesterol synthes's in a negative direction. Different nicotinic acid compounds can have the same effect as nicotinic acid in proportion to their capability of generating nicotinic acid and active nicotinic acid metabolites. There can be considerable difierences in this respect. In order to obtain a clinical effect under pathological conditions, a continuously satisfactory blood level is of great importance. It is known that merely moderate doses of nicotinic acid gives a very high blood level, of short dura tion, followed by a rapid secretion of different metabolites, primarily in the form of N-methyl nicotinic acid. The eflFect of this high, transient content of nicotinic acid in the blood involves considerable side effects in the form of heavy flushing and heat, with prickliness in the skin. Many esters of nicotinic acid give the same rapid resorption and side effects as the nicotinic acid itself, and are, consequently, not clinically unobjectionable pharmaceuticals. An ester which does not have these side effects is meso-ino sitol hexanicotinate, which has thereby also become widely used clinically. Owing to its symmetrical constitution and comparatively high molecular weight, this compound has the property that it can be successively hydrolyzed and/or resorbed in vivo, and a continuously raised nicotinic acid level in the blood then occurs. This gives improved metabolic conditions when there are pathological disturbances of the energy metabolism in living tissue. By means of resorption investigations on human beings, it has been possible to determine that the meso-inositol hexanicotinate is not totally resorbed when passing through the alimentary canal, even if a significant rise of the nicotinic acid level in the blood and the metabolite in the urine takes place. The resorption in patients which have been checked was approx. 75%

The purpose of the present invention is to make better use of an ester of the type meso-inositol hexanicotinate, which has been introduced. Extensive investigations have shown that if, by means of a mineral acid or a strong organic acid, the meso-inositol hexanicotinate is hydrolyzed to such an extent that with removed side chains of nicotinic acid derivates, a nitrogen content of approx. and a melting point within the interval of 120130 3,418,325 Patented Dec. 24, 1968 ICC C. is obtained, the nicotinic acid preparation obtained, when used, will cause a resorption, in the patients checked, of no less than In spite of the improved resorption, the disadvantage of the flushing effect and prickliness does not occur.

The reason for the improved resorption must be that if a nicotinic acid preparation of the type meso-inositol hexanicotinate is used, the nicotinic acid is secreted from this preparation more easily when a side chain has been removed from the beginning.

The invention will be described in more detail in the following examples:

Example 1 810 g. of meso-inositol hexanicotinate is dissolved in 8 litres of Water and approx. 600 g. of hydrochloric acid, specific gravity 1.19, to a pH of approx. 1. The solution is treated at a temperature of approx. 20 C. for 40 hours through slow stirring. When the reaction time is over, the solution is carbon treated with an addition of versinate for complex binding of any heavy metal ions, filtered and neutralized with a 25% solution of ammonia, bicarbonate, carbonate or some other appropriate alkali solution, until a pH of at least 6.5 has been reached. The reaction product is then precipitated, and is filtered oil? and washed with water. The product obtained, after drying, has shown beginning sintering at l43145 C., and an equivalent weight of 141.8 and a nitrogen content of 9.95%. The yield was 91% of the theoretical yield. Part of the hydrolyzed nicotinic acid can be recovered from the mother liquid, through evaporation and adjustment of the pH to 3.5, which is the isoelectric point of the nicotinic acid.

Example 2 810 g. of meso-inositol hexanicotinate is dissolved in 8 litres of Water and approx. 300 g. of sulfuric acid, specific gravity 1.84, to a pH of 1.1. After 40 hours of treatment at approx. 20 C., the reaction product is worked up as per Example 1, and the same yield and data is then obtained.

We claim:

1. An ester of meso-inositol and nicotinic acid having a nitrogen content of about 10.0% and a melting point of about 130 C. which is prepared by stirring mesoinositol hexanicotinate in an aqueous solution containing a mineral acid or a strong organic acid at a temperature of about 20 C. for a period of about 40 hours and bringing the solution to a pH of about 6.5 to precipitate the product.

2. An ester of meso-inositol and nicotinic acid according to claim 1, wherein the mineral acid is hydrochloric acid.

3. An ester of meso-inositol and nicotinic acid according to claim 1, wherein the mineral acid is sulfuric acid.

References Cited Badgett et al.: I. Am. Chem. Soc., vol. 69, p. 2907 (1949).

Donatelli et al.: Chem. Abstracts I, vol. 49, 1956, par. 3390b and 3391a.

Seckfort et al.: Chem. Abstracts II, vol. 54, par. 25, 270 1960).

HENRY R. JILES, Primary Examiner.

A. L. ROTMAN, Assistant Examiner.

U.S. Cl. X.R. 16765 

